Glycidamides for inducing a sedative response

ABSTRACT

2-Phenylglycidamides such as 3-chloro-2-(2,4-dichlorophenyl) glycidamide, are described. The compounds have utility in the polymer field and also possess useful biological activity.

W D Q mtefi Slates Patent 1 1 3,726,982

i [451 Apr. 10, 1973 [54] GLYCIDAMIDES FOR INDUCING A [56] References Cited SEDATIVE RESPONSE 1 OTHER PUBLICATIONS [75] Inventor: Carolyn M. Quick, Manteca, Calxf. M J Am Ch S V l 6 N t 1 [73] Assignee: Shell Oil Company, New York, NY. pp 5 0c 0 5 o 2 22] Filed: Oct. 8, 1971 Primary Examiner-Jerome D. Goldberg 2 7 Attorney-Frank R. LaFontaine et a1.

Related US. Application Data [62] Division of Ser. No. 5,109, Jan. 22, 1970, Pat. No. [57] ABSIRACT 2-Phenylglycidamides such as 3-chloro-2-(2,4 dichlorophenyl) glycidamide, are described. The com- ILS. 4

have in the polymer and also p0 Int. Cl. ..A61k 27/00 $685 f l biological activity Field of Search....,.,.... .......424/278 4 Claims, No Drawings GLYCIDAMIDES FOR INDUCING A SEDATIVE RESPONSE This application is a division of Ser. No. 5,109, filed Jan. 22, 1970, now US. PaLNo. 3,646,211.

, BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION It is an object of this invention to provide novel and useful Z-phenylglycidamides. It is another object to provide novel Z-phehylglycidamides possessing utility in the polymer field and having activity as nervous system depressants. Accordingly, this invention is a novel class of 2-phenylglycidamides.

DESCRIPTION OF THE-PREFERRED EMBODIMENTS The novel class of compounds of this invention can be described by the formula wherein X .is hydrogen or halogen, Y is hydrogen, halogen or alkyl of 1-4 carbon atoms, Zis halogen, nitro, alkyl of l-4 carbon atoms, trifluoromethyl or alkylsulfonyl of l-4 carbon atoms, H is hydrogen and n is 1, 2, or 3,'with the provisos that when n is less than 3, each Z may be the same or different and when Y is alkyl, X is hydrogen.

The alkyl moieties may be straight or branched-chain and include methyl, ethyl, isopropyl, butyl and the like.

The halogens are fluorine, chlorine, bromine and iodine.

Mainly because of availability of the starting materials and ease of. snythesis the 2-phenylglycidamides of the following formula form a preferred subclass:

NHa

The alkyl moieties may be straight or branched-chain and include methyl, ethyl, isopropyl, butyl and the like.

Exemplary compounds within this subclass include:

when R is chlorine or bromine;

3 -chloro-2-( 2-chlorophenyl glycidamide 3 ,3-dichloro-2-(2,3-dichlorophenyl)glycidamide,

3-bromo-2-(2,3-dichloro-4-propylphenyl)glycidamide,

3-ethyl-2-(2-chloro-3,4-difluorophenyl)glycidamide,

2-( 2-bromo-4-ethylphenyl)glycidamide,

2-(2-chloro-3-methylphenyl)glycidamide, I

2-(2,3-dichloro-4-fluorophenyl)glycidamide,

3-chloro-3-bromo-2-( 2-chloro-4-propylphenyl)glycidamide,

2-( 2-chlorophenyl)glycidamide,

3-methyl-2-( 2-chloro-3-methylphenyl)glycidamide,'

3-chloro-2-( 2-chloro-3,4-dimethylpheny[)glycidamide,

2-( 2-chloro-4-trifluoromethylphenyl)glycidamide,

3chloro-2-(2-chloro-3-trifluoromethylphenyl)g lycidamide and the like;

7 when R, is chlorine or bromine;

' 2-(4 -chlorophenyl)glycidamide,

2(3,4-dichlorophenyl)glycidamide, 3-chloro-2-(4-bromophenyl)glycidamide, 3,3-dichloro-2-(2-methyl-4-chlorophenyl)glycidamide,

3-ethyl-2-(2-methyl-3,4-dichlorophenyl)glycidamide,

3 -bromo-2-( 3 ,4-dichlorophenyl)glycidamide,

3-chloro-2-(2-butyl-3,4-dichlorophenyl)glycidamide,

v3-chloro-2-( 2-fluoro-4-bromophenyl)glycidamide,

3-chloro-2-(2,3-difluoro-4-chlorophenyl)glycidamide,

3chloro-2-(2,3-dimethyl-4-chlorophenyl)glycidamide,

3-chloro-2-(3-ethyl-4-bromophenyl)glycidamide,

3-bromo-2-( 2-fluoro-3 methyl-4-chlorophenyl)glycidamide,

2-( 2-trifluoromethyl-4-chlorophenyl)glyciamide,

3'-chloro-2-( 3-trifluoromethyl-4-chlorophenyl)glycidamide and the like;

and when R: and R are chlorine or bromine;

2-(2,4-dichlorophenyl)glycidamide,

2-(2,3,4-trichlorophenyl)glycidamide, 2(3-methyl-2,4-dichlorophenyl)glycidamide, 3-chloro-2-(2,4-dibromophenyl)glycidamide,

v 3-chloro-2-(3-fluoro-2,4-dichlorophenyl)glycidamide,

3,3-dichloro-2-(2,3,4-trichlorophenyl)glycidamide, 3-methyl-2-(2,4-dichlorophenyl)glycidamide,

3-butyl-2-( 3-methyl-2,4-dichlorphenyl )glycidamide 2-(2,4-dichloro-B-trifluoromethylphenyl)glycidamide,

3-chloro-(2,4-dichloro-3-trifluoromethylphenyl)glycidamide and the like.

Within the Z-phenylglycidamides of formula II, a particularly preferred subclass because of their activity as nervous system depressants, especially as sedatives, hypnotics and anticonvulsants, are those where R is hydrogen or chlorine, preferably hydrogen, R, is hydrogen, chlorine or bromine, preferably chlorine, R

is chlorine or methyl, R is hydrogen or chlorine,

preferably hydrogen, and R is hydrogen, chlorine,

fluorine or methyl, with the proviso that at least one of R and R4 is chlorine. This is the most preferred subclass of the compounds of the invention.

Preferred species are:

3-chloro-2-(2,4-dichlorophenyl)glycidamide 3-chloro-2(2-chloro-4-fluorophenyl)glycidamide 3-chloro-2-(2-chlorophenyl)glycidamide 3-bromo-2-(2,4-dichlorophenyl)glycidamide 3-chloro-2-(2-methyl-4-chlorophenyl)glycidamide 3-chloro-2-(2-chloro-4-methylphenyl)glycidamide 2(2,4-dichlorophenyl)glycidamide 3,3-dichloro-2-(2,4-dichlorophenyl)glycidamide When the compounds of the invention contain different atoms substituted at the 3-position, i.e., X and Y are different, two stereoisomers can exist. It is to be understood that these isomers as well as mixtures of the two are within the scope of this invention.

The 2-phenylglycidamides of the invention find utility in the polymer field. For example, they are especially advantageous as modifiers of epoxy resins, particularly the glycidyl polyether resins such as are described and claimed in U.S. Pat. No. 2,633,458 with which they can be mixed in proportions of about 1:10 to 1:1 and cured in the usual way to obtain products of controlled properties, esepcially as regards flexibility. Those 2-phenylglycidamides containing halogen have the additional advantage of acting as fire-retardants when mixed with such epoxy resins and cured.

The most preferred subclass, as previously described,

' are particularly valuable as nervous system depressants, especially as hypnotics, sedatives and anticonvulsants.

Preparation The 2-phenylglycidamides of this invention, except for those of formula 1 in which Y is alkyl of 1-4 carbon atoms, may be prepared by reaction of the appropriate a-(halomethyl)mandelamide with sodium hydroxide, sodium methoxide or sodium hydride. These (halomethyl)mandelamides, in turn, are readily prepared by the hydrolysis of the corresponding 0:- (halomethyl)mandelonitriles with 80-95 percent sulfuric acid at temperatures of from about 80110C, preferably about 95C. The q-(halomethyl)mandelonitriles are prepared by the known method of reacting the corresponding 2-haloacetophenones with hydrogen cyanide in the presence of a small amount of potassium cyanide as catalyst.

The 2-haloacetophenones may be prepared by a variety of methods. Most may be prepared by the well known Friedel-Crafts acylation of the appropriately substituted benzene with acetyl chloride or the appropriate monoor dihaloacetyl chloride. The 2-position of the appropriately ring-substituted acetophenone may be halogenated to form the 2,2- dihaloacetophenones using the appropriate halogen in formic acid. The 2,2,2-trihaloacetophenones may be prepared by the free-radical halogenation of the appropriate 2,2-dihaloacetophenone.

The 3-alkyl substituted 2-phenylglycidamide may be parpared by the alkaline peroxide oxidation of the appropriate B-alkylatroponitrile; these fi-alkylatroponitriles, in turn, may be prepared by the base catalyzed condensation of the appropriate substituted benzylcyanide and aldehyde. These procedures are described more fully by Knowles et al., J. Am. Chem. Soc., 54 2028 (1932) and Vigier et al., Bull. Soc. Chim. France, 677 (1963).

As previously mentioned, those 2-p henylgly cidamides substituted by two different atoms at the 3-position are capable of existing in two geometrically isomeric forms. For purposes of this invention those isomeric pairs that were separated have been designated as either a or B. The B isomers were those that were the major component of the isomeric pair, generally were the lower melting, and had the longer chromatographic retention times on silica gel G. The a isomers conversely were the minor component of the isomeric pair and had shorter chromatographic retention times. The a isomers also tended to be more unstable relative to the fi isomer of the pair. The stereochemical configurations of the a and B isomers were'not determined.

The following examples are illustrative of the methods used to prepare the compounds. of this invention. In these examples, parts" means parts by weight unless otherwise expressly indicated, and parts by weight bear the same relationship to parts by volume as does the kilogram to the liter. All elemental analyses are based on percent by weight.

EXAMPLE 1. Preparation of haloacetophenones a. 2,2,2, 4', 5'-Pentachloroacetophenone To a stirred slurry of 176 parts aluminum chloride in 218 parts 1,2,4-trich1orobenzene at 60C was added dropwise over 15 minutes 176 parts dichloroacetyl chloride. The reaction mixture was stirred at 90C for 4 hrs., cooled and poured into 2000 parts by volumes of ice containing parts by volume concentrated hydrochloric acid. The aqueous mixture was extracted with ether. The combined extracts were washed with 1N hydrochloric acid, 5 percent aqeuous sodium bicarbonate, saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Stripping of the solvent afforded 309 parts crude brown liquid which upon distillation gave 264 parts (76 percent) light yellow, 2,2,2',4',5-pentachloroacetophenone, b.p. 1 l7-123C at 0.7 mm. The product was identified by infrared spectral analy- SIS.

Cl Anal. Calc'd for C,H,Cl,0: 60.7 Found: 61.3

b. 2,2,2'-Trichloroacetophenone Chlorine gas was bubbled into a stirred solution of 68 parts 2'-chloroacetophenone in 240 parts by volume glacial formic acid at 30C containing a small amount of dissolved hydrogen chloride. The reaction was continued for 4 hours while the temperature slowly rose to 50C. After standing overnight the reaction mixture was poured into water and the product was extracted with methylene chloride. The extracts were washed with 5 percent sodium bicarbonate solution and water, and dried with anhydrous magnesium sulfate. Solvent removal afforded 96 parts (98 percent) of slightly yellow liquid, 2,2,2-trichloroacetophenone. The produce was identified by infrared sepctral anaylsis.

c. 2,2 ,2 ,2 ,4-Pentachloroacetophenone Chlorine gas was slowly added over 30 hrs. with stirring to 307 parts 2,2,2',4'-tetrachloroacetophenone undergoing ultraviolet irradiation. The reaction temperature was maintained at l55-l60C. The product was stripped under high vacuum to give 347 parts (100 percent) of the yellow liquid, 2,2,2,2',4'tachl( infrared spectral analysis.

EXAMPLE 2. 3+Chloro-2-(2,4- dichlorophenyl)glycidamide (a and B isomers) a. 2,4-Dichloro-a-(dichloromethyl)mandelonitrile 2,2,2,4-Tetrachloroacetophenone (202 parts) obtained ,by the usual Friedel-Crafts reaction from mdichlorobenzene and dichloroacetyl chloride dissolved in 80 parts by volume of liquid hydrogen cyanide at C was treated with 15 drops of a freshly prepared potassium cyanide solution. A vigorous exothermic reaction occurred causing reflux of the hydrogen cyanide. After 15 minutes-refluxing, 100 parts by volume of ether and 4 parts by volume of concentrated sulfuric acid were added. The ether and excess hydrogen cyanide were removed by distillation and the resultant solid was recrystallized from hexanezbenzene (19:1) to give 187 parts of 2,4-dichloro-a-(dichloromethyl)mandelonitrile as a white solid melting at 9395C,

identified by elemental analysis:

N Cl Anal. Calc'd for N0|.C,H.= 4.9 49.8 Found: 5.2 50.0

b. The nitrile from (a) above (300 parts) in 1000 parts by volume of 80 percent sulfuric acid was heated on a steam bathfor 16 hours, cooled and poured over ice. The resultant gummy precipitate was dissolved in methylene chloride, dried and cooled to 'give 258 parst were identified by elemental and infrared spectral anaylses.

N Cl Analysis Calcd for NO,CI,C H,: 5.3 39.9 Found for isomer (3) m.p. 122123C 5.3 39.7 Found for isomer (0:) m.p. 170-l71C 5.3 39.7

d. To a stirred solution of 60.6 parts of the amide from (b) above in 175 parts by volume of anhydrous methoanol was added dropwise a solution of 10.8 parts of sodium methoxide in 100 parts by volume of anhydrous methanol. The resulting solution was stirred at room temperature for 6 hours and allowed to stand overnight. The reaction mixture was poured into water and extracted with methylene chloride. The extracts were washed with water, dried with anhydrous magnesium sulfate and the solvent removed to afford a crude mixture of the two isomers as in method (0) above, which when chromatographed and recrystallized gave 34.3 parts of the B isomer, melting at 122124C and 1.7 partsof the a isomer melting at l69.5170C, which were identified by Nuclear Magof 2,4-dichloro-a-(dichloromethyl)mandelamide melting at 135-137C. This was identified by infrared spectral analysis. y

c. To a stirred suspensionof 2.4 parts of hexanewashed percent sodium hydride-mineral oil suspension in 50 parts by volume anhydrous tetrahydrofuran was added all at once a solution of 15 parts of .the amide from (b) aobve in parts by volume of anhydrous tetrahydrofuran. An exothermic reaction occurred with hydrogen evolution and the formation of a white precipitate. The reaction mixture was stirred for 6 hours, poured into water, and extracted with ether. The ether extracts were washed with water, dried with anhydrous magnesium sulfate and the solvent was removed to afford a yellow viscousliquid. Recrystallization from methylene chloride/hexane gave 6 parts white crystals, m.p. -12lC, containing a mixture of two isomers in a 6:1 ratio. Chromatographic separation of the mixture followed by recrystallization gave 3.1 parts of the 3 isomer (melting at 122-123.C) and 0.4 parts of the a isomer (melting at 17017l.5C) of netic Resonance and infrared spectral analyses.

EXAMPLE 3. 2-(2,4-Dichlorophenyl)-3- propylglycidamide of liquid 2,4-dichloro-B-propylatroponitrile, b.p. 125-128C at 0.05 mm.

' N C1 Anal. Calcd for C,,H,,CI,N: 5.8 29.6

Found: 5.6

b. A stirred mixture of 6.0 parts of the nitrile of (a) above, 5 parts by volume 30 percent hydrogen peroxide, 10 parts by volume sodium carbonate solution and 30 parts by volume acetone were heated at 52C for 30 minutes. Cooling, filtration of the resultant white crystals and recrystallization from ethanol gave 3.5 parts of 2-(2,4-dichlorophenyl)-3-propylglycidamide, m.p. 16l162C. The original filtrate afforded an additional 2.5 parts 2-(2,4-dichlorophenyl(-3-propylglycidamide, m.p. -161C from a hexane-benzene mixture. The total yield was 6.0 parts (88 percent).

Using the procedures of Examples l-3 the following 2-phenylglycidamides were prepared. The resultsare summarized in Table I. The compounds are identified 3-chloro-2-(2,4-dichlorophenyl)glycidamide which by the following formula:

Z llNllz Y 'lAlHl'l l l llvnmlli=1l analysis Compound Z X Y M.l., (J. N (:1 vHr Eu. S (3 11 N ()1 ltr I S (J H 4 2411 ll. Cl [3 101-104 0.0 30.5 5.8 3L0 TABLE 1 ('onlinucd l'llomvnlnl analysis lsollul Compound Z X mvr N l llr liq. S ll 5 J-(ll 11 (ll 6.8 31.!) 6 l-Cl 11 (-l [i 5.1! 31.8 7.... 4-Cl ll (31 a 5.!) 31.8

l-|il' ll (ll {3 4.8 14.5 l-lll ll (.1 a t. 4.7 13.0 4-1" H (l [i 1;. 1) 16. 2+ IJHJ ll (3| /1 7.3 110.0 l-l'Hu ll l 5.1) Ill. illahi); H (71 {i 5.0 13.5 F ll (.11 [i 5.1 10.1 i l[ ()1 a 175. 5-177 5.3 5.2 10. (i ll. ()1 B 98-91) 6.0 6. 0 14.1! Cl 11 Cl 6 141.6-143 4. 7 4. 5 47. 18 Cl 11 Cl a 2 4. 7 4. 6 47. 1! -Cl 11 Cl 6 131.5-135 4.6 4.11 47. 2 Cl 11 C1 or 162. 5-166 4. 6 4. 5 48. 21 2-Cl,4-F 11 Cl (3 9Gl02 5. 6 5. G 28. .Z-Cl,4-F 11 Cl a 168-170 5. 6 .5. 5 .28. 2,5-Cl II II 186.5-190 (i. 0 (i. l .20. 2,4-Cl H 11 124-127 (1. 0 5. 30. 2,4-01 H Br 139-1405 4. 5 4. 3 21. 2,4-Cl H Br 2,4-Cl H 1l-CaH7 S-NO: H H 2,4-C C1 C1 2-CI13A-Cl 11 Cl [5 Z-CHVl-Cl 11 Cl 11 2-(Il,4-C111 11 Cl 6 2-01/1-0111 II Cl (1 1 or and [1 mixture. 2 Crude liquid.

Nervous System Depressant Activity The hyponotic activity of these glycidamides was noted as follows. Mice were orally intubated with 500 mg/kg* of the test compound and observed at 15 minutes, 1 hour, 2 hours, 4 hours and 24 hours. Pharmacotoxic signs, especially onset and termination of the loss of righting reflex, were noted. Any compound inducing a loss in the righting reflex in 50 percent of the mice at any of these test intervals was considered active and were tested. at lower oral doses and/or by intraperitoneal injection. Two reference drugs, Glutethimide and sodium pentobarbital, were included in the tests as controls. The results of the tests are shown in Table 11.

TABLE II Approx.OralApprox Hypontic Activity Test lethal Hypnotic lntraperitoneal Compound Dose Dose Rating at 180 mglkg s s s s Zfi 500 62 -HH- 4 500 250 -H+l- 17 500 500 -H+ 21 500 500 +H+ 24 25 4+ 29 500 inactive 30 500 250 +t-H- 31 -H- 32 500 inactive -l+H- Glutethimide 560 180 H Pentobarbital-Na 500 125 +-Hl- 2B refers to beta isomer prepared in Example 2; other numbers refer to compounds of Table l.

l-2 mice, -H-= 3-6 mice, -Hl-= 7-9 mice and -lH-+= 10 mice out of 10 exhibited hypnotic activity.

a at 100 mg/kg, not tested at 180 mglkg.

4 All mice died.

5 9 out of a total of 9 mice tested exhibited hypnotic response.

' 2 out of a total of 5 mice tested exhibited hypnotic response.

1 Based on mean response of 1 1 groups of 10 animals.

In addition to the hypnotic activity, compound 2a was also shown to exhibit other nervous system depressant effects. These include minor tranquilizing activity' as shown by the pernicious preening test of Wilfon, J. G. et al., Fed. Proc., 19, 20 (1960); skeletal muscle relaxant activity as shown by antagonism to the lethal effect of intravenous injection of styrchnine sulfate; and,.lastly, antagonism of supra-maximal electroshock 30 seizure test of Swinyard, E. A., J. Am. Pharm. Assoc.

38, 201 (1949). The results of these tests are sown in Table 111 in comparison with the reference compounds, Glutethimide and sodium pentobarbital. The data show that compound 23 is more active and also has a greater safety factor (i.e., the ratio of LD ,:ED is larger) than the two reference compounds,

Compositions according to the present invention also comprise a pharmaceutical carrier which may either by solid material or a liquid. Preparations for oral adminis- 40 tration can be liquids or solids or any combination of these forms, such as syrups, elixirs, powders, capsules, or tablets. Preparations for administration of the active agent in unit dose form can be powders, compressed tablets, or a powder enclosed in a suitable capsule of absorbable material such as gelatin. The powders or compressed tablets may also comprise suitable excipients and/or diluents such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinyl-pyrrolidone.

Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water, physiological saline, polyethylene glycol, mineral oil, ethyl oleate, methylcellulose, dimethyl sulfoxide or other liquid excipients known in the pharmaceutical and veterinary formulations art.

The unit dosage or therapeutically effective quantity of the glycidamides used according to this invention as analgesics, muscle relaxants, anticonvulsants and/or tranquilizers can vary over wide limits. For oral or parenteral administration in some cases, as little 10 milligrams of the active material per kilogram of body weight can be effective in the reduction of pain or in effecting sedation and muscle relaxation, while seldom will a dosage in excess of about 200 milligrams per kilogram of body weight be required. In general, for oral administration the effective dosage will be from about 15 to 200 milligrams per kilogram of body weight, while for parenteral administration, the effective dosage will be from about 1 to 100 milligrams per kilograms of body weight. The hypnotic dose for the oral route is about 40 milligrams per kilogram of mammal body weight and the hypnotic dose for the wherein X is hydrogen or halogen, Y is hydrogen, halogen or alkyl of 1-4 carbon atoms, Z is halogen, 3- nitro, alkyl of 14 carbon atoms, trifluoromethyl or 4- alkylsulfonyl of 1-4 carbon atoms, H is hydrogen and n parenteral route is 40 milligram per kilogram of mam- 5 is a whole number from one to three; with the provisos mal body weight. Each dosage unit form each capthat when n is less than 3, each Z may be the same or sule, tablet, ampoule, or prescribed dose can contain "different, and when Y is y X is y g from about 1 percent to about 95 percent of acti 2. A method of inducinga sedative response in mammaterial, based upon the total weight of the fo l mals comprising administering to a mammal in need of tion and preferably contains from about 2.5 percent to such treatment an effective dosage for inducing a sedaabout 50 percent of the active mineraLon the same balive response Ofa compound of the formula: sis. Of course, it is possible to administer the therapeutics without the use of a pharmaceutical carrier; The therapeutic agents used according to the inven- RP Q tion can -be administered either prior to or after the J3 onset of the conditionto be treated, such as when they a are used as: analgesics for the amelioration of pain; motor depressants or tranquliizors to relieve nervoius tension; central depressants to reduce hyperexcitability wherein R is chlorine, bromine or hydrogen, R is and induce sedation {or as muscle relaxants for relief chlorine, bromine, hydrogen or alkyl of l-4 carbon from pain and discomfort of disorders involving muscle atoms, and R R and R,, which may be the same or spasms. v different, are fluorine, chlorine, bromine, hydrogen,

- TABLE III n Minoi' tranquilizing lAntistryehnlne Maximal electroactivity l.p. activity i.p., mgJkg. shock i.p., mgJkg.

. EDau ao E1350 I Test compound (mg/kg.) LDm/EDlso (mg/kg.) LDm/EDsn (mg/kg.) LDm/ED mg./kg

2a. 3615 14 24.7 21 '24.7 21 510 Glutethimide 100 5. 6 75 7. 5 560 Pentobarbital-Nuqnu 56 2. 3 39 3. 3 39 3. 3 136 Iclaim as my invention: trifluoromethyl or alkyl of l-4 carbon atoms; with the 1. A method of inducing a sedative response in mamprovisios that at least one of R and R is chlorine or mals comprising administering to a mammal in need of bromine and that when R is alkyl, R is hydrogen. 7 such treatment an effective dosage for inducing a seda- 3. The method according to claim 2 wherein R is tive response ofa compound of the formula hydrogen or chlorine, R, is hydrogen, chlorine or bromine, R, is chlorine or methyl, R is hydrogen or 0 chlorine, and R is hydrogen, chlorine, fluorine or 40 methyl; with the proviso that at least one of R and R is Z chlorine. l 'Y 4. The method according to claim 3 wherein R, R

NH; and R are hydrogen and R, and R are'chlorine.

(Z) 4-n V a a m r I u 

2. A method of inducing a sedative response in mammals comprising administering to a mammal in need of such treatment an effective dosage for inducing a sedative response of a compound of the formula:
 3. The method according to claim 2 wherein R is hydrogen or chlorine, R1 is hydrogen, chlorine or bromine, R2 is chlorine or methyl, R3 is hydrogen or chlorine, and R4 is hydrogen, chlorine, fluorine or methyl; with the proviso that at least one of R2 and R4 is chlorine.
 4. The method according to claim 3 wherein R, R1 and R3 are hydrogen and R2 and R4 are chlorine. 